A multi-institutional team has added
more than 20 pathogens to the list of known bacteria that express poly-N-acetylglucosamine, a bacterial capsule polysaccharide that provides a
potentially broad-spectrum target for vaccination.1 The findings
open up new indications for Alopexx Vaccine LLC and Alopexx Pharmaceuticals LLC, which are already developing a vaccine and an antibody
for passive immunization, respectively.

Over
the past two decades, studies by multiple groups have identified poly-N-acetylglucosamine
(PNAG), a polysaccharide encoded by a
conserved four-gene locus, as a component of the surface capsule in at least
seven species of bacteria.2-7

PNAG
is one of many polysaccharides and other carbohydrate polymers found on the
outer surface of bacteria that help prevent host macrophages and other cells from
engulfing the pathogens.

Anti-PNAG
antibodies have been found in circulation in humans and other animals, but
these naturally occurring antibodies do not effectively kill PNAG-expressing
bacteria or provide adequate immune protection against them, casting doubts on
their prophylactic potential.8-10

Between
2005 and 2007, teams led by Gerald Pier showed that a deacetylated form of PNAG
(dPNAG) elicited bacteria-killing antibodies in mice.6,11 His teams
also developed a human mAb-dubbed F598-that bound to both dPNAG and PNAG
and killed bacteria.12

In the current study, Pier's team investigated whether
PNAG was expressed on bacteria and other pathogens in which the four-gene
PNAG-producing locus has not yet been identified.

The group used F598 conjugated to a fluorescent agent to
detect PNAG on the surfaces of pathogens and found the molecule in 24 pathogens
not previously known to express it. Among the new pathogens were
disease-causing bacteria such as Streptococcus pneumoniae, Clostridium
difficile and Mycobacterium tuberculosis, as well as the yeast Candida
albicans and the parasite Plasmodium falciparum (see "Adding pathogens to the PNAG list")

Lastly, the team tested the protective effect of the mAb
in mice challenged with selected pathogens. In mice exposed to C. albicans,
N. meningitidis, S. pneumoniae, S. pyogenes or P.
burghei,pretreatment with the mAb led to decreased symptoms of eye
infection, meningitis, lung infection, skin infection or cerebral malaria,
respectively, compared with pretreatment with a control antibody or control
serum.

"Our new study extends the list of PNAG-expressing
organisms to most major human pathogens, including 9 of the top 10 causes of
nosocomial infections" as reported by the Centers for Disease Control and Prevention
(CDC), Pier told SciBX (seeTable 2 "Nine out of ten for PNAG"). "This implies
that a PNAG
vaccine or passive immunotherapy with the anti-PNAG antibody
could target a huge range of organisms with just one inoculation or treatment."

Pier noted that Pseudomonas aeruginosa is the
only bacterium on the CDC's top 10 list that does not express PNAG.

Data were reported in Proceedings of the National
Academy of Sciences.

"The new study underscores that we have something
unusual and even unique in our PNAG vaccine," said Daniel Vlock. "First,
we have a target that is expressed incredibly broadly in pathogens. Second, we
can produce the vaccine via chemical synthesis, which is certainly cleaner than
recombinant methods, and we hope it will be simpler and cheaper as well."

In 2006, Pier and Vlock cofounded Alopexx
Pharmaceuticals to develop F598 as a passive immunotherapy to protect against
bacterial infections. Four years later, the duo cofounded Alopexx Vaccine,
which has the dPNAG-based vaccine AV0318 in preclinical
development to prevent bacterial infections in humans and production animals.

Vlock is CEO of both companies, which are part of the
group Alopexx Enterprises LLC,
which provides investment, managerial and development capabilities to its
multiple subsidiaries.

In
4Q13, Alopexx Vaccine plans to begin testing AV0318 in cows to prevent mastitis
caused by S. aureus and Escherichia coli and in pigs to prevent a
severe form of pneumonia caused by Actinobacillus pleuropneumoniae,
Vlock said.

"The
immunogenicity and any toxicity we see in these animals will have an impact on
what we can do in humans," he added.

Alopexx
Vaccine expects to begin a Phase I trial of AV0318 in humans next year. Vlock
declined to disclose the target populations or indications.

Meanwhile,
Pier's team is testing F598 in vitro and in animals challenged with E.
coli K1, Group B Streptococcus and other pathogens that cause neonatal
infections in humans.

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